Total Synthesis of Anticancer Natural Products Using Oxidative Dearomatization

氧化脱芳构全合成抗癌天然产物

• 批准号: 9171740
• 负责人: Yu Yuan
• 金额: $ 43.62万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171740
• 关键词: Academic Research Enhancement Awards; Alkaloids; Ally; Antineoplastic Agents; Basic Science; Biological; Biology; Cancer Patient; Carbon; Cause of Death; Cells; Cephalotaxus; Cessation of life; Chemicals; Complex; Data; Development; Dose; Drug Industry; Economic Burden; Electron Transport; Electrons; Elements; Exhibits; Family; Intercept; Investigation; Laboratories; Longevity; Lymphoma; Malignant Neoplasms; Medical; Methodology; Methods; Mus; Natural Products; Navelbine ditartrate; Nerve Growth Factors; Norditerpenoids; Octanes; Organic Synthesis; Outcome; Oxidants; Paclitaxel; Patients; Phenols; Positioning Attribute; Protocols documentation; Radiation therapy; Reaction; Reagent; Regimen; Reporting; Research; Science; Scientist; Skeleton; Societies; Solid Neoplasm; Structure; Structure-Activity Relationship; System; Testing; Therapeutic Agents; United States; United States Food and Drug Administration; Up-Regulation; Vasodilation; alkaloid skeleton; analog; anticancer activity; base; chemotherapy; cycloaddition; cytotoxicity; diene; experience; improved; member; neoplastic cell; novel; novel therapeutics; operation; outcome forecast; oxidation; scaffold; skills; stereochemistry

PROJECT SUMMARY Cancer is the second leading cause of deaths in the United States and it has become a serious economic burden to society. Among the most successful treatments, natural product inspired chemotherapies such as Paclitaxel, Navelbine and Eribulin have significantly extended the life span of millions of cancer patients. It has been reported that more than 75% of the new chemical entities submitted to the Food and Drug Administration as anticancer agents between 1940 and 2010 have natural product origins. We propose to develop a novel oxidative dearomatization methodology to access the core structures of biologically active natural products and investigate its application to the total synthesis of daphmanidin A, an alkaloid showing significant cytotoxicity against murine lymphoma cells. Because some subtypes of lymphoma do not form solid tumors, their treatments commonly involve intense radiotherapy and chemotherapy. To improve the prognosis of patients who show low tolerance to current high dose regimens, new therapeutic agents with better efficacy are urgently needed. Given the cytotoxicity profiles of Daphniphyllum alkaloids, it is important to study the biology of daphmanidin A and explore its potential to become a therapeutic agent. Our preliminary data have shown that an enantioselective Michael addition / oxidative dearomatization cascade can be achieved by a one-pot operation, and the desired products are obtained with excellent stereoselectivity and yields, highlighting the remarkable efficiency of our strategy for the synthesis of these natural products. When para substituted phenols are subjected to the dearomatization, the core structures of Cephalotaxus norditerpenes are conveniently produced. When ortho substituted phenols are intercepted during the dearomatization, the spiro intermediates can serve as dienes in the subsequent [4+2] cycloaddition, resulting in the daphmanidin A type alkaloid skeletons. In the proposed research we will 1) identify the suitable single electron transfer reagent and base to enable the dearomatization for sensitive substrates under homogenous conditions; 2) study the regioselectivity for asymmetrically substituted aromatics; 3) examine the conditions to intercept spiro diene in the dearomatization; 4) elucidate the stereochemistry determining elements that control the chirality of the quaternary carbon center, and 5) apply the novel methodology to the synthesis of daphmanidin A and its pharmaceutically relevant analogues.

项目摘要 癌症是美国的第二大死亡原因，它已成为一个严重的疾病。 社会的经济负担。在最成功的治疗方法中，天然产品启发了 化疗，如紫杉醇，诺维本和艾日布林显着延长了寿命， 数百万癌症患者。据报道，超过75%的新化学实体 在1940年至2010年期间提交给食品和药物管理局作为抗癌药物的药物， 天然产品的起源我们建议开发一种新的氧化脱芳构化方法， 生物活性天然产物的核心结构，并研究其在总 对鼠淋巴瘤细胞显示显著细胞毒性的生物碱瑞香素A的合成。 由于淋巴瘤的某些亚型不形成实体瘤，因此其治疗通常涉及 强烈的放疗和化疗。改善低耐受性患者的预后 对于目前的高剂量方案，迫切需要具有更好疗效的新治疗剂。给定 因此，研究虎皮楠生物碱的生物学特性具有重要意义 并探索其成为治疗剂的潜力。 我们的初步数据表明，对映选择性迈克尔加成/氧化脱芳构化反应， 可以通过一锅操作实现级联，并且获得具有优异性能的所需产物。 立体选择性和产率，突出了我们的战略，用于合成的显着效率 这些天然产品。当帕拉取代的酚进行脱芳构化时， 可以方便地制备红豆杉去甲二萜结构的化合物。当邻位取代的酚 在脱芳构化过程中被拦截，螺环中间体可以在脱芳构化过程中充当二烯。 随后的[4+2]环加成，产生了瑞香素A型生物碱骨架。拟议 研究我们将1）确定合适的单电子转移试剂和碱，使 在均相条件下对敏感底物的脱芳构化反应; 2）研究 不对称取代的芳族化合物; 3）检查在不对称取代的芳族化合物中拦截螺二烯的条件。 脱芳构化; 4）阐明控制手性的立体化学决定因素， 季碳中心，以及5）将新方法应用于合成瑞香素A及其 药学相关的类似物。